The broad long-term research objective of this project is to understand the causes and clinical significance of variation in developmental stability among individuals. Variation in developmental stability is correlated with stress, inbreeding, teratologies and a growing number of other developmentally based pathologies. An important step in understanding how developmental stability relates to abnormal development is to understand the causes of normal variation in developmental stability. The most common measure of developmental stability, fluctuation asymmetry (FA), refers to normally distributed deviations across planes of organismal symmetry. This question is approached by studying patterns of variation in FA of skeletal structures during prenatal development of the mouse limb. Comparisons are also made with variation in adult skeletal structures. This project has four specific aims. 1) The first will determine how FA of limb skeletal elements changes during prenatal development. This aim addresses the question of whether imprecision in development arises through the cumulative effects of minor perturbations on an initially precise substrate or whether it represents the degree to which regulatory mechanism guide an initially sloppy process towards a precise end. 2) The second specific aim will determine whether postnatal patterns of variation in developmental instability among skeletal structures can be embryologically determined. 3) The third specific aim will determine whether variation in developmental rate is related to developmental instability. Through sub-hypotheses that address the significance of overall developmental rate, overall coordination of rates, and character specific variation in developmental rate, this aim will tet the proposition that developmental instability derives from breakdown in the internal coordination of developmental rates. Since developmental disorders linked to developmental disorders linked to developmental instability (e.g. cleft palate) may involve breakdown in the timing-coordination of related developmental processes, this proposition may bridge the gap between the association of developmental stability time or rate and its association with abnormal development. 4) The fourth specific aim examines the effect of specific mutations on FA in limb skeletal structures. If breakdown in the internal coordination of developmental rates causes developmental instability, then mutations that affect overall and region-specific growth rates should increase FA. Production of double-mutants with both regional and global defects will determine whether these effects are additive.